Percutaneous transluminal coronary angioplasty (hereinafter referred to as "PTCA") is a therapeutic technique recently developed for nonsurgical treatment of coronary artery diseases. Thus, the technique comprises mechanically dilating the stenosed coronary artery by means of an inflatable balloon. However, PTCA cannot be a radical treatment of coronary artery diseases. It is known that in about 40% of the cases treated by PTCA for coronary stenosis, restenosis occurs several months after operation. Reportedly, this restenosis is mainly caused by cellulofibrous hyperplasia of the intima due to migration of smooth muscle cells from the media to the intima upon stimulation by various factors (platelet-derived growth factor, thrombin, etc.) resulting from platelet aggregation and blood clotting at the site of injury by PTCA and the subsequent proliferation of the smooth muscle cells in the intima [British Heart Journal, 58, 635-643 (1987); Human Pathology, 20, 477-485 (1989)].
To prevent this restenosis, various drugs including anticoagulants such as heparin, etc., platelet aggregation inhibitors such as aspirin, dipyridamole, ticlopidine, prostacyclin and its derivatives, etc., cell proliferation inhibitors such as ketanserin, and antilipidemics such as eicosapentaenoic acid, lovastatin, etc. have been tested preclinically or clinically but none of them proved to be sufficiently effective from the clinical viewpoint [inter alia, American Heart Journal, 117, 777-782 (1989); ibid., 119, 232 (1990); ibid., 122, 171-187 (1991); Circulation, 81, 1753-1761 (1990); Lancet, 177-181 (1989)].
With heparin, in particular, it has been reported that its long-term use (10,000 units/day, s.c.) following coronary angioplasty resulted in coronary restenosis in 82% of the cases, a very high figure as compared with control (restenosis value: 33%), with abnormal hemorrhage supervening in 41% [Journal of American College of Cardiology, 17 (2), 181A, (1991)]. This augmentation of bleeding tendency has been cited as one of the adverse effects of heparin, and heparin may cause not only hemorrhage at the administration site but also bleeding in the gastrointestinal tract and, in serious cases, even intracranial hemorrhage, with death from massive loss of blood ensuing in the worst cases.
Meanwhile, it is known that sulfated polysaccharides containing a heparin fragment which consists of 2 to 8 heparin- or haparan sulfate-derived saccharide units have a proliferation inhibitory action on smooth muscle cells (Japanese Kohyo Tokkyo Koho H04-503950 and H06-506973). Those heparin fragment-containing compounds, which are deprived of the antithrombin III-mediated antithrombin activity of heparin [Blood, 79, 1-17 (1992)], are expected to be attenuated in the bleeding-promoting effect based on the antithrombin activity of heparin. However, since the inhibition of abnormal smooth muscle proliferation by heparin in vivo is considered to involve, as one of the mechanisms thereof, said antithrombin III-mediated antithrombin activity, deprivation of this activity is considered to detract from the smooth muscle proliferation inhibitory effect.
Under the circumstances, development of a drug which would inhibit post-PTCA restenosis of the coronary arteries and hence intimal hyperplasia in atherosclerosis and be of clinical value has been awaited.